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Table 1 Genes predisposing to syndromic infertility

From: Genes predisposing to syndromic and nonsyndromic infertility: a narrative review

Gene Locus Biological functions Some mutations reported Pathophysiology/disorders
CFTR (cystic fibrosis transmembrane conductance regulator) 7q31.2 CFTR transports chloride ions into and out of cells, controlling the movement of water in tissues, which is necessary for the production of mucus that lubricates and protects the lining of the airways, digestive system, reproductive system, and other organs and tissues [12]. A 3-bp deletion named F508del, 5 T single nucleotide polymorphism (SNP) within intron 8, 7 T SNP within intron 8, and missense mutation named R117H within exon 4 were reported [13]. Others are G542X, G551D, R553X, W1282X, and N1303K [13, 14]. It causes CBAVD, which causes a disconnection between the epididymis and the ejaculatory duct, leading to obstructive azoospermia [13]. Also causes cystic fibrosis (CF), which is associated with menstrual irregularities, including amenorrhea, irregular cycles, and anovulation [15].
NR5A1 (nuclear receptor subfamily 5 group A member 1) 9q33.3 NR5A1 produces a transcription factor called the steroidogenic factor 1 (SF1), which helps control the activity of several genes related to the development of ovaries and testes, particularly the production of sex hormones and sexual differentiation [16]. A missense heterozygous mutation involving c. 3G → A transition and two heterozygous frameshift mutations named c. 666delC and c. 390delG were reported [17]. The following were also reported: p. Pro311Leu, p. Arg191Cys, p. Gly121Ser, p. Asp238Asn, and p. Gly123Ala/p. Pro129Leu [18], as well as a heterozygous mutation named c. 195G > A [19]. Predisposes to Swyer syndrome, which disrupts sexual differentiation and prevents affected 46, XY male from developing testes and causing them to develop a uterus and fallopian tubes [16]. Because of the lack of development of the gonads, Swyer syndrome is also called 46, XY complete gonadal dysgenesis. In females, mutations in the gene cause several ovarian anomalies, including 46, XX gonadal dysgenesis [16].
WT1 (Wilms’ tumor 1) 11p13 The gene is a transcription factor that is expressed in the kidneys, ovaries, and testes [20] and functions in gonadogenesis. Particularly, it plays an active role in ovarian follicle development [21] and spermatogenesis [22]. A heterozygous point mutation in intron 7 named +2, T → G was reported [23]. R362Q and K386R missense mutations among Chinese population [22].
Moreover, Seabra et al. [24] reported p. Pro130Leu and pCys350Arg missense mutations among Portuguese. Two heterozygous missense mutations named p. Pro126Ser in exon1 and p. Arg370His in exon7 were also reported among the Chinese women [25]. A variant named IVS+4C>T has also been reported [20].
The +2, T → G mutation causes Wilms’ tumor, characterized by congenital male genitourinary malformation [23]. R362Q and K386R missense mutations cause loss of function of the WT1 protein, resulting in non-obstructive azoospermia [22]. The p. Pro126Ser and p. Arg370His missense mutations cause premature ovarian follicles (POF) [25]. Some mutations also cause Frasier syndrome and Denys-Drash syndrome, both of which often affect the male kidney and genitalia development [20].
FMR1 (fragile X mental retardation 1) Xq27.3 The FMR1 encodes a protein called FMRP, which is expressed in the brain, testes, and ovaries. FMR1 transmits nerve impulses in the brain. In the cell, it transports mRNA from the nucleus to the sites where proteins are assembled, some of which are necessary for the functioning of the nerves, testes, and ovaries [26]. A region of the gene contains a CGG trinucleotide repeat of less than 10 to about 40. However, the FMR1 mutation has been reported in which the CGG was abnormally repeated from 200 to more than 1000 times [26]. Abnormal CGG expansion causes instability in the region, deactivating the gene and making little or no protein, resulting in a condition called fragile X syndrome characterized mainly by mental retardation [26]. CGG elongation between 55 and 200 repeats causes POF [27] and fragile X-associated primary ovarian insufficiency (FXPOI) [26]. FXPOI is characterized by irregular menstrual cycles, early menopause, and elevated levels of follicle-stimulating hormone (FSH) [26].
GALT (galactose-1-phosphate uridylyltransferase) 9p13.3 The gene synthesizes galactose-1-phosphate uridylyltransferase, which converts galactose obtained from food into glucose, the main fuel for all cellular activities. This chemical reaction also produces an active form of galactose known as UDP-galactose, which is used to build galactose-containing proteins and fats, both which are involved in energy production, chemical signaling, cell structure building, and molecule transport [28]. The SNP called Gln188Arg or Q188R is prevalent among white Europeans and North Americans [28]. Another SNP called Ser135Leu or S135L are found mostly among the African descent [28]. The SNP named Asn314Asp or N314D was also reported [28]. It represses or stops the activity of the galactose-1-phosphate uridylyltransferase, preventing cells from converting galactose into glucose. Consequently, galactose-1-phosphate and related compounds build up to toxic levels in the body, damaging tissues and organs, and leading to a condition known as galactosemia [28]. Women with galactosemia express hypergonadotropic hypogonadism and secondary amenorrhea [29], as well as ovarian failure [30].
GDF9 (growth/differentiation factor 9) 5q31.1 This gene encodes a transforming growth factor-beta superfamily, which is necessary for ovarian folliculogenesis and somatic cell function [30, 31]. Several missense mutations reported [32]. It elevates the levels of serum gonadotropins and reduces estradiol, predisposing to premature ovarian failure 14 (POF14), an ovarian disorder defined as the cessation of ovarian function under the age of 40 years. The condition is characterized by oligomenorrhea or amenorrhea [33]. Altered expression of the gene is also associated with polycystic ovary syndrome (POS) [31].
MED12 (mediator complex subunit 12) Xq13.1 The MED12 gene codes for a protein called mediator complex subunit 12, which regulates gene activity by linking transcription factors with an enzyme called RNA polymerase II. The MED12 protein is involved in several chemical signaling pathways that control many cellular activities, such as cell growth, cell movement, and cell differentiation [34]. Several somatic mutations in the MED12 gene have been reported [34]. It causes uterine leiomyomas, which are noncancerous growths also known as uterine fibroids. Uterine leiomyomas are common among adult women and cause pelvic pain, abnormal bleeding, and, in some cases, infertility [34]. MED12 mutations produce nonfunctional protein, which disrupts normal cell signaling and impairs regulation of cell growth and other cell functions. As a result, certain cells divide uncontrollably, leading to the growth of a tumor [34].
ANOS1 (anosmin 1)/KAL1 Xp22.31 The gene encodes a protein called anosmin-1, which is involved in embryonic development. Anosmin-1 is expressed in the brain and involved in the migration of neurons that produce gonadotropin-releasing hormone (GnRH), which controls the production of several hormones that direct sexual development before birth and during puberty, such as the ovaries and testes functions [35]. Mutations that delete a part or the entire gene, as well as SNPs that alter or change amino acids in anosmin-1, have been reported [35], among which is c.1267C>T [36]. Alters the synthesis or function of anosmin-1 during embryonic development, resulting in the loss of sense of smell and the production of sex hormone, respectively, and the latter interferes with normal sexual development causing absence or delay of puberty [35]. Mutations in the gene also predispose to Kallmann syndrome, a disorder characterized by hypogonadotropic hypogonadism [35]. Males expressing hypogonadotropic hypogonadism often have an unusually small penis (micropenis), undescended testes, and lack of secondary sex characteristic, while females fail to menstruate and develop breast [35].
LEP (leptin) 7q32.1 The gene codes for leptin, which is a hormone that takes part in body weight regulation [37], metabolism, and puberty [38], as well as cell signaling that regulates sex development hormones [37]. Complete deletion of the gene has been reported in infertile humans and rats [38]. A SNP named rs10244329 was also reported [39]. Causes congenital leptin deficiency, a disorder that causes the absence of leptin, resulting in the loss of signaling that triggers feelings of satiety, leading to excessive hunger and weight gain, reduced production of hormones that direct sexual development, and ultimately ending in hypogonadotropic hypogonadism [37].
LEPR (leptin receptor) 1p31.3 The gene synthesizes a protein called leptin receptor, which is embedded in many tissues, including the hypothalamus, and helps regulate body weight by providing binding sites for leptin [40]. At least 18 LEPR gene mutations have been reported [40]. Results in less receptor protein reaching the cell surface, causing a condition called leptin receptor deficiency, which reduces LEPR protein binding and signaling activities as well as satiety, resulting in excessive hunger and weight and reduced sex hormones, culminating in hypogonadotropic hypogonadism [40].
NR0B1 (nuclear receptor subfamily 0 group B member 1)/AHC (adrenal hypoplasia congenital) Xp21.2 The NR0B1 gene codes for a transcription factor called DAX1, which is involved in the development and function of several hormone-producing (endocrine) tissues, including the adrenal glands, hypothalamus, pituitary gland, as well as the ovaries and testes [41]. Complete and partial deletions of the gene have been reported [41]. Abnormally short versions of the DAX1 protein as well as SNPs have also been reported [41]. Produces inactive DAX1 protein, disrupting normal development and function of hormone-producing tissues, particularly the adrenal glands, hypothalamus, pituitary, and gonads, resulting in a condition called X-linked adrenal hypoplasia congenital [41], characterized by male puberty delay [38]. Mutations in this gene also cause Swyer syndrome [41].
HESX1 (HESX homeobox 1) 3p14.3 The HESX1 gene encodes a transcription factor that regulates the early embryonic development of several body structures, particularly the pituitary gland [42]. SNPs as well as insertion and deletion mutations have been reported in this gene [42]. Alters the function of the HESX1 protein and represses the activity of other genes, disrupting the formation and early development of the pituitary gland, optic nerves, and other brain structures, resulting in gonadotropin deficiency and a condition known as septo-optic dysplasia [42]. Septo-optic dysplasia is characterized by hypogonadotropic hypogonadism [38].
LHβ (luteinizing hormone beta-subunit) 19q13.33 It encodes the beta subunit of luteinizing hormone (LH), which is expressed in the pituitary gland and promotes spermatogenesis and ovulation by stimulating the testes and ovaries to synthesize steroids [43]. The SNP named G1052A has been reported [44]. Six other SNPs were also identified and are gC356090A, gC356113T, gA356701G, gG355869A, gG356330C, and gG356606T [45]. Causes defective LH, leading to low testosterone and gonadotropins, culminating in pubertal delay, bilaterally small descended testes, and infertility [38]. Also increases susceptibility to PCOS, characterized by pubertal delay [38].
LHCGR (luteinizing hormone/choriogonadotropin receptor) 2p16.3 The gene synthesizes the luteinizing hormone/chorionic gonadotropin receptor which is a receptor for luteinizing hormone and chorionic gonadotropin. In males, chorionic gonadotropin stimulates the development of Leydig cells in the testis, which are also stimulated by luteinizing hormone to produce androgens, such as testosterone that controls male sexual development and reproduction. In females, luteinizing hormone triggers ovulation, while chorionic gonadotropins ensure normal progression of pregnancy [46]. A SNP called G935A has been reported [44]. At least 17 other SNPs were reported [46]. Impairs the development of LHCGR protein, preventing chorionic gonadotropin binding, and resulting in the absence, or poorly developed Leydig cells, a condition called Leydig cell hypoplasia, characterized by low testosterone, which interferes with male sexual development before and after birth [46]. Extreme Leydig cell hypoplasia causes 46, XY male to develop female external genitalia and small undescended testes [46]. Mild Leydig cell hypoplasia results in an external genital that is not clearly male or female [46]. Mutations in the gene also cause polycystic ovary syndrome (POS) [46].
AR (androgen receptor) Xq12 The AR gene produces an androgen receptor, which is expressed in many tissues, where it binds to androgen to form an androgen-receptor complex, which in turn binds to DNA and regulates the activity of certain genes involved in male sexual development [47]. Abnormal elongation of a DNA segment in the AR gene known as CAG, which is normally repeated between less than 10 and 36, has been reported [47]. Some SNPs, as well as deletions and insertions, were also reported [47]. Results in the receptors that are unable to bind androgens or DNA, causing androgen insensitivity syndrome (AIS), a condition that causes male sexual dysfunction before birth and at puberty. The condition also causes 46, XY male sex reversal also known as gonadal dysgenesis [47]. Mutations in the gene also cause polycystic ovary syndrome [47].
SRY (sex-determining region Y) Yp11.2 The gene encodes a transcription factor called the sex-determining region Y protein, which is located on the Y chromosome and regulates genes involved in male sexual activities, directing a fetus to develop testes and preventing uterus and fallopian tube formation [48]. Absence and rearrangement that wrongly placed the gene on the X chromosome have been reported [48]. Prevents production of SRY protein or hampers it, resulting in Swyer syndrome, characterized by 46, XY male sex reversal [48]. Sometimes the mutation may misplace the gene on the X chromosome from the father, causing 46, XX female to develop both ovarian and testicular tissues, a condition called ovotesticular disorder [48].
VDR (vitamin D receptor) 12q13.11 The gene is expressed in male and female reproductive tissues [49] and synthesizes a protein called vitamin D receptor, which forms a complex with an active form of vitamin D, known as calcitriol, and another protein called retinoid X receptor, which then binds to particular regions of DNA, where it regulates the activity of some genes that control several processes, particularly calcium and phosphate absorption [50]. In mice, VDR signaling plays a role in folliculogenesis and fertility [51]. The SNP in exon 9 named rs731236 was reported by Bagheri et al. [52]. Szczepańsk et al. [53] also reported two SNPs named rs1544410 and rs222857. Reduces follicle number, resulting in PCOS [51, 52] or endometriosis-associated infertility [53]. VDR knockout in female mice disrupts VDR signaling and ovarian response to stimulation, causing defective folliculogenesis and infertility [51]. Male mice deficient of VDR showed gonadal insufficiency and decreased sperm count and motility as well as histological abnormalities of the testis [49].
FKBP4 (FKBP prolyl isomerase 4) 6p21.3 The gene encodes FKBP52, which plays an important role in potentiating androgen receptor (AR) signaling in the prostate and accessory glands [54]. Deletions and two SNPs, known as rs2968909 and rs4409904, were reported [55]. Causes azoospermia [54] as well as implantation failure and recurrent pregnancy [56]. Also predisposes to PCOS [55].
DBY (DEAD-box Y RNA helicase)/DDX3Y (DEAD-box helicase 3 Y-linked) Yq11.21 The gene resides in the AZFa region on the Y chromosome and is expressed in many tissues, but mostly in the spermatogonia of the testis tissue and translated only in the male germline [57]. Deletion mutations were reported [57]. Causes severe testicular pathology known as Sertoli cell-only (SCO) syndrome, a condition that disrupts spermatogenesis [57].
USP9Y (ubiquitin specific peptidase 9 Y-linked) Yq11.221 USP9Y resides in the azoospermia factor a (AZFa) region of the Y chromosome and encodes an enzyme called ubiquitin-specific peptidase 9, Y-linked, which is necessary for sperm production [58]. AZFa deletions resulting in complete loss of USP9Y have been reported [59]. Predisposes to Sertoli cell-only syndrome, characterized by the absence of germ cells in the seminiferous tubules, leading to azoospermia [59]. Also causes spermatogenic failure Y-linked 2 (SPGFY2), resulting in azoospermia or oligozoospermia [59].
PLK4 (Polo-like kinase 4) 4q28.1 PLK4 protein resides in the centrioles and plays an active role in centriolar duplication that is necessary for normal cell division [60, 61]. A heterozygous mutation called p.Ile242Asn was observed in mice [62]. A heterozygous 13 bp deletion called c.201_213delGAAACATCCTTCT was also reported [62]. Causes mitotic error in mice, resulting in patchy germ cell loss in the testes similar to the human Sertoli cell-only syndrome (SCOS) [62, 63].
BBS9 (Bardet-Biedl syndrome 9)
PTHB1 (parathyroid hormone responsive-B1)
7p14 The specific role of the protein released by this gene has not been determined [64]. A haplotype named GAAAG as well as three SNPs named rs3884597, rs6944723, and rs11773504 were reported [65]. Causes Bardet-Biedl syndrome, characterized by many features, including POF [65].
FSHR (follicle-stimulating hormone receptor) 2p16.3 The gene secretes a receptor for the follicle-stimulating hormone, which functions in the ovary and testis development [66]. A SNP in exon 7 named C566T and involving Ala to Val substitution at residue 189 was reported by Aittomäk [67]. Predisposes to ovarian dysgenesis 1 (ODG1), characterized by primary amenorrhea, poorly developed streak ovaries, and high serum levels of FSH and LH. May also cause ovarian hyperstimulation syndrome (OHSS), characterized by massive ovarian enlargement as well as multiple serous and hemorrhagic follicular cysts lined by luteinized cells [68].